Effect of weight loss on intermuscular adipose tissue (IMAT) signaling

减肥对肌间脂肪组织 (IMAT) 信号传导的影响

• 批准号: 10735418
• 负责人: BRYAN C BERGMAN
• 金额: $ 65.75万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-05 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10735418
• 关键词: Achievement; Adipose tissue; Age; Attenuated; Bathing; Biopsy; Body Weight decreased; Body mass index; Clinical; Closure by clamp; Data; Development; Diabetes Mellitus; Eicosanoids; Ethnic Origin; Extracellular Matrix Proteins; Fibronectins; Future; Glucose Clamp; Health; Human; Hyperinsulinism; In Vitro; Individual; Inflammation; Inflammatory; Inflammatory Response; Insulin; Insulin Resistance; Intervention; Life; Magnetic Resonance Imaging; Marble; Measures; Metabolic; Metabolic dysfunction; Mission; Muscle; Muscle Fibers; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Obesity; Outcome; Paracrine Communication; Play; Positioning Attribute; Public Health; Research; Risk; Role; Sampling; Signal Transduction; Signaling Molecule; Skeletal Muscle; Techniques; Testing; Tissues; United States National Institutes of Health; Visceral; adipokines; combat; cytokine; disability; experimental study; improved; innovation; insulin sensitivity; lifestyle intervention; new therapeutic target; novel; obese person; obesity risk; prevent; response; sex; therapeutic target; therapy development; ultrasound; weight loss intervention

Intermuscular adipose tissue (IMAT) is marbled within skeletal muscle and appears to play a key role in the obesity-induced risk of type 2 diabetes. What is not known is how IMAT promotes decreased muscle insulin sensitivity. There is a critical need to understand how IMAT contributes to the risk of obesity-induced diabetes, and how to intervene to minimize IMAT-induced muscle metabolic dysfunction. The overall objective for this project is to determine the impact of weight loss on IMAT secretion of fibronectin and inflammatory cytokines and eicosanoids. Our central hypothesis is that IMAT secretion of fibronectin promotes muscle insulin resistance, and IMAT secretion of inflammatory cytokines and eicosanoids causes muscle inflammation, both of which are diminished by weight loss. The rationale that underlies the proposed research is that clarifying the extent to which weight loss alters the IMAT secretome will inform development of interventions to modify IMAT and improve muscle insulin sensitivity in obese individuals. We propose two specific aims: Specific Aim 1. Evaluate the impact of weight loss on IMAT secretion of fibronectin and the role of fibronectin in the IMAT secretome to decrease insulin sensitivity in vitro. Preliminary data inform our working hypothesis that IMAT secretes fibronectin that decreases muscle insulin sensitivity and is attenuated after weight loss in humans. In vitro experiments will measure the extent to which IMAT fibronectin secretion explains IMAT-induced muscle insulin resistance. We will study individuals with obesity before and after a 12-week weight loss intervention. IMAT will be sampled using an ultrasound guided IMAT biopsy technique, insulin sensitivity measured using insulin clamps, and IMAT content measured using MRI. Specific Aim 2 – Determine the influence of weight loss on IMAT secretion of pro-inflammatory cytokines and eicosanoids and potency to cause inflammation and decrease insulin sensitivity in vitro. We hypothesize, again based on preliminary data that the IMAT secretome is less inflammatory after weight loss in obese individuals, with decreased potency to promote muscle inflammation and insulin resistance. Muscle inflammatory response and insulin sensitivity with IMAT secretome exposure will be compared before and after weight loss in vitro. The proposed research is innovative because it represents a new and substantive departure from the status quo by testing specific IMAT secreted paracrine signals rather than clinical associations with IMAT content. These contributions will be significant by identifying the first IMAT paracrine signals that impact muscle and revealing the plasticity of IMAT through weight loss, providing proof of concept that IMAT is a therapeutic target to combat muscle metabolic dysfunction.

肌间脂肪组织（IMAT）是骨骼肌内的大理石状组织，似乎在骨骼肌中发挥着关键作用。 肥胖导致的2型糖尿病风险。目前尚不清楚IMAT是如何促进肌肉胰岛素减少的 灵敏度迫切需要了解IMAT如何增加肥胖诱发糖尿病的风险， 以及如何干预以最大限度地减少IMAT诱导的肌肉代谢功能障碍。总体目标是 该项目旨在确定体重减轻对IMAT分泌纤维连接蛋白和炎症细胞因子的影响 和类二十烷酸。我们的中心假设是，IMAT分泌的纤连蛋白促进肌肉胰岛素 抵抗，以及炎性细胞因子和类花生酸的IMAT分泌导致肌肉炎症， 其中的一部分因体重减轻而减少。所提出的研究的基本原理是，澄清 体重减轻改变IMAT分泌组的程度将为干预IMAT的发展提供信息 并改善肥胖个体的肌肉胰岛素敏感性。我们提出两个具体目标：具体目标1。 评价体重减轻对IMAT分泌纤连蛋白的影响以及纤连蛋白在IMAT中的作用 分泌蛋白酶体降低体外胰岛素敏感性。初步数据告诉我们的工作假设，IMAT 分泌纤维连接蛋白，降低肌肉胰岛素敏感性，并在人体体重减轻后减弱。在 体外实验将测量IMAT纤连蛋白分泌在多大程度上解释IMAT诱导的肌肉 胰岛素抵抗我们将研究12周减肥干预前后的肥胖患者。 将使用超声引导IMAT活检技术对IMAT进行采样，使用 胰岛素钳和使用MRI测量的IMAT含量。具体目标2 -确定重量的影响 - 促炎细胞因子和类花生酸的IMAT分泌以及引起炎症的效力的丧失， 降低体外胰岛素敏感性。我们再次根据初步数据假设IMAT分泌组 在肥胖者减肥后炎症较少，促进肌肉生长的效力降低 炎症和胰岛素抵抗。肌肉炎症反应和胰岛素敏感性与IMAT分泌蛋白 将在体外体重减轻之前和之后比较暴露。这项研究具有创新性，因为 它代表了一个新的和实质性的偏离现状，通过测试特定的IMAT分泌旁分泌 信号而不是与IMAT内容的临床关联。这些贡献将是重要的， 第一个IMAT旁分泌信号影响肌肉并通过体重减轻揭示IMAT的可塑性， 提供了IMAT是对抗肌肉代谢功能障碍的治疗靶点的概念证明。